Abstract Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for pain but there is no class 1 study on its role in migraine prophylaxis. In this study we report the efficacy and safety of high-rate rTMS in migraine prophylaxis. Adult migraine patients having[4 attacks/month were randomized to high-rate rTMS or sham stimulation. Stimulation in the form of 10 Hz rTMS, 600 pulses in 10 trains were delivered to the hot spot of the right abductor digiti minimi in 412 s. Three sessions were delivered on alternate days. The outcome was defined at 1 month. The primary outcome measures were reduction in headache frequency and severity[50 % as assessed by the Visual Analogue Scale (VAS). The secondary outcome measures were functional disability, rescue medication and adverse events. Fifty patients each were randomized to rTMS or sham stimulation. The baseline characteristics of rTMS and sham stimulation groups were similar. At 1 month, headache frequency (78.7 vs. 33.3 %; P = 0.0001) and VAS score (76.6 vs. 27.1 %; P = 0.0001) improved significantly in the patients receiving rTMS compared to those in the sham stimulation group. Functional disability also improved significantly in rTMS group (P = 0.0001). Only one patient following rTMS developed transient drowsiness and was withdrawn from the study. This study provides evidence of the efficacy and safety of 10 Hz rTMS in migraine prophylaxis.

Transcranielle Magnetstimulation bei Depression

The Efficacy and Safety of Low Frequency Repetitive Transcranial Magnetic Stimulation for Treatment-resistant Depression: The Results From a Large Multicenter French RCT

Context:
The aim of this study was to assess whether the combination of low frequency repetitive transcranial magnetic stimulation (rTMS) and venlafaxine (150
e 225 mg/day) is effective and safe for treatment-resistant unipolar depression (TRD).

Method:
In a multicenter (18 centers) randomized double blind controlled trial with three arms, 170 patients were allocated to receive active rTMS combined with active venlafaxine ( n ¼ 55), active rTMS combined with placebo venlafaxine (n ¼ 60) or sham rTMS combined with active venlafaxine ( n ¼ 55). The patients received once daily sessions of active or sham 1 Hz rTMS applied over the right dorsolateral prefrontal cortex (360 pulses/day delivered at 120% of the resting motor threshold) for two to six weeks; rTMS was combined with active or sham venlafaxine (mean dose: 179.0 36.6 mg/day). The primary outcome was the number of patients who achieved remission, which was defined as an HDRS 17 score < 8.

Results:
We reported a similar significant antidepressant effect in the 3 groups (P<
106), with a comparable delay of action and a comparable number of remitters at the endpoint (28% in the combination group, 41% in the rTMS group and 43% in the venlafaxine group; P ¼ 0.59).

Conclusion:
Low frequency rTMS appears to be as effective as venlafaxine and as effective as the combination of both treatments for TRD. Because of its short session duration (the duration of one session was 8.5 min) and its safety, slow rTMS might be a useful alternative treatment for patients with TRD. Ó 2014 Elsevier Inc. All rights reserved.

Meta-Review of Metanalytic Studies with Repetitive Transcranial Magnetic Stimulation (rTMS) for the Treatment of Major Depression

Major Depression (MD) and treatment-resistant depression (TRD) are worldwide leading causes of disability and therapeutic strategies for these impairing and prevalent conditions include pharmacological augmentation strategies and brain stimulation techniques. In this perspective, repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique with a favorable profile of tolerability which, despite being recently approved by the Food and Drug Administration (FDA) for the treatment of patients with medication-refractory unipolar depression, still raises some doubts about most effective parameters of stimulation. Methods: A literature search was performed using PubMed for the years 2001 through February 2011 in order to review meta-analytic studies assessing efficacy and safety issues for rTMS in depressive disorders. Fifteen meta-analyses were identified and critically discussed in order to provide an updated and comprehensive overview of the topic with specific emphasis on potentially optimal parameters of stimulation. Results: First meta-analyses on the efficacy of rTMS for the treatment of MD and TRD have shown mixed results. On the other hand, more recent meta-analytic studies seem to support the antidepressant efficacy of the technique to a greater extent, also in light of longer periods of stimulation (e.g. > 2 weeks). Conclusion: rTMS seems to be an effective and safe brain stimulation technique for the treatment of medication refractory depression. Nevertheless, further studies are needed to better define specific stimulation-related issues, such as duration of treatment as well as durability of effects and predictors of response.

The Effects of Repetitive Transcranial Magnetic Stimulation on Cognitive Performance in Treatment-Resistant Depression. A Systematic Review.

Major depressive disorder (MDD) is a disabling illness associated with significant functional and psychoso- cial impairment. Although many psychopharmacological agents are currently available for its treatment, many MDD patients suffer from treatment-resistant depression (TRD). Methods: A systematic review of the current literature (Pubmed/Medline, Scopus and ScienceDirect search) has been conducted with the primary aim to investigate the role of repetitive transcranial magnetic stimulation (rTMS) in im- proving neurocognition in patients with TRD. Studies were included according to the following criteria: (a) being an original paper in a peer-reviewed journal and (b) having an- alyzed the effect of rTMS on neurocognitive functioning in TRD. Results: The combined search strategy yielded a total of 91 articles, of which, after a complete analysis, 22 fulfilled our inclusion criteria. Based on the main findings, most of the selected studies suggested the existence of a trend towards improvements in the neurocognitive profile using rTMS. Negative findings have also been reported. However, most studies were limited by their small sample size or included mixed samples, or the adopted single-blind designs poten- tially biased the blinding of the study design. Conclusion: rTMS is a noninvasive brain stimulation that may be consid- ered a valuable and promising technique for cognitive enhancement in TRD.

Theta Burst Stimulation at 50Hz and 20Hz for TMS Treatment of Depression: A Case Series

New Targets for rTMS in Depression A Review of Convergent Evidence

Although rTMS is moving steadily into the mainstream as a treatment for medically refractory depression, its efficacy continues to lag behind that of more invasive neuromodulation treatments such as ECT or DBS. Here we review evidence to suggest that a fruitful, but neglected, strategy for improving rTMS efficacy may be to explore alternatives to the conventional stimulation target in the dorsolateral prefrontal cortex (DLPFC). The convergent evidence of lesion, stimulation, connectivity, and correlative neuroimaging studies suggests that the DLPFC may have a relatively peripheral role in mood regulation, at least compared to several alternative areas within the prefrontal cortex. In particular, we consider the evidence base in support of four new potential targets for rTMS in depression: dorsomedial prefrontal cortex (DMPFC), frontopolar cortex (FPC), ventromedial prefrontal cortex (VMPFC), and ventrolateral prefrontal cortex (VLPFC). Each of these regions enjoys broader support, from a more diverse evidence base, than the DLPFC in terms of its role in emotion regulation in major depression. We discuss the relative merits of each of these novel targets, including potential obstacles to stimulation using currently available technologies, and potential strategies for overcoming these obstacles. It is hoped that this detailed review will spur a more vigorous exploration of new targets for rTMS in depression. The use of new targets may help to propel rTMS across the threshold of efficacy required of a first-line treatment, to assume a more widespread role in the treatment of depressed mood.

Transcranielle Magnetstimulation in der Psychiatrie

Should We Expand the Toolbox of Psychiatric Treatment Methods to Include Repetitive Transcranial Magnetic Stimulation (rTMS)? A Meta-Analysis of the Efficacy of rTMS in Psychiatric Disorders

Objective: Repetitive transcranial magnetic stimulation (rTMS) is a safe treatment method with few side effects. However, efficacy for various psychiatric disorders is currently not clear. Data sources: A literature search was performed from 1966 through October 2008 using PubMed, Ovid Medline, Embase Psychiatry, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, and PsycINFO. The following search terms were used:transcranial magnetic stimulation, TMS, repetitive TMS, psychiatry, mental disorder, psychiatric disorder, anxiety disorder, attention-deficit hyperactivity disorder, bipolar disorder, catatonia, mania, depression, obsessive-compulsive disorder, psychosis, posttraumatic stress disorder, schizophrenia, Tourette’ s syndrome, bulimia nervosa, and addiction. Study selection: Data were obtained from randomized, sham-controlled studies of rTMS treatment for depression (34 studies), auditory verbal hallucinations (A VH, 7 studies), negative symptoms in schizophrenia (7 studies), and obsessive-compulsive disorder (OCD, 3 studies). Studies of rTMS versus electroconvulsive treatment (ECT, 6 studies) for depression were meta-analyzed. Data extraction: Standardized mean effect sizes of rTMS versus sham were computed based on pretreatment-posttreatment comparisons. Data synthesis: The mean weighted effect size of rTMS versus sham for depression was 0.55 (P<.001). Monotherapy with rTMS was more effective than rTMS as adjunctive to antidepressant medication. ECT was superior to rTMS in the treatment of depression (mean weighted effect size−0.47, P =.004). In the treatment of AVH, rTMS was superior to sham treatment, with a mean weighted effect size of 0.54 (P<.001). The mean weighted effect size for rTMS versus sham in the treatment of negative symptoms in schizophrenia was 0.39 (P=.11) and for OCD, 0.15 (P=.52). Side effects were mild, yet more prevalent with high-frequency rTMS at frontal locations. Conclusions: It is time to provide rTMS as a clinical treatment method for depression, for auditory verbal hallucinations, and possibly for negative symptoms. W e do not recommend rTMS for the treatment of OCD. ??? The first modern transcranial magnetic stimulation (TMS) device was developed during the early 1980s by Barker et al. The device creates a strong pulse of electrical current which is sent through a coil and which induces a magnetic field pulse in a small area underlying the coil. When applied over the skull, this pulse has the capacity to depolarize local neurons up to a depth of 2 cm. TMS can be used as a brain-mapping tool, as a tool to measure cortical excitability, as a probe of neuronal networks, and as a modulator of brain function. When repetitive TMS (rTMS) pulses are applied, a longer lasting effect can be induced which is thought to result from a long-term potentiation or depression at the neuronal level. High frequent rTMS can induce an epileptic seizure, which is a dangerous side effect. However, since the introduction of specific safety guidelines, rTMS is considered a safe treatment method. Its side effects are generally mild. They include headache, local discomfort as a consequence of direct stimulation of the facial musculature, and transient changes in the auditory threshold. To prevent this latter side effect, the use of earplugs is recommended. Initially, rTMS was investigated chiefly as a tool for the treatment of depression. A few years later, it was explored by Hoffman and colleagues for the treatment of auditory verbal hallucinations (AVH). Further research with rTMS has involved the experimental treatment of mood disorders, negative symptoms of schizophrenia, obsessive-compulsive disorder (OCD), Tourette’s syndrome, posttraumatic stress disorder, panic disorder, Alzheimer’s disease, bulimia nervosa, conversion, catatonia, and various forms of substance addiction. Twenty-three years after its introduction, the number of publications reporting on the effects of rTMS treatment in psychiatric disorders has increased dramatically (263 published studies between 2000 and June 2008, as compared to 26 between 1990 and 2000). This 10-fold increase in the number of publications was accompanied by an even larger increase in sample size, which developed from single cases to samples of over 100 patients in recent publications. Furthermore, the US Food and Drug Administration approved rTMS for the treatment of depression in October 2008. Due to its mild side effects and its relatively low costs, rTMS tends to be considered an attractive therapeutic tool. The TMS equipment can be obtained at the price of approximately €25,000, and the stimulation technique is relatively easy to acquire. However, mental health professionals may hesitate to embrace rTMS as a routine treatment method because its efficacy is as yet uncertain. A number of meta-analyses quantified the effects of rTMS for depressive disorder, but even these results are ambiguous. As the effect sizes of these studies differed substantially, no general conclusions can be drawn. More details are presented in the Discussion. The effects of rTMS treatment in AVH has been meta-analyzed once before, indicating a moderate mean effect size. No meta-analyses have been published on the effects of rTMS for other psychiatric disorders or symptom clusters. According to Loughlin et al and Kozel et al, the mean costs of an rTMS treatment for depression, consisting of 15 treatment sessions, are £1,444 and $1,422, respectively. The duration of the effect of rTMS is as yet unknown, but for an effect of 4 months, the mean costs of antidepressant agents for the same period lie around $110. The question remains whether patients benefiting from medication are comparable with patients having rTMS treatment. In our opinion, the data currently available do not allow for any firm conclusions about the costs of rTMS versus medication. This review aims to assess the value of rTMS as a therapeutic tool for psychiatric disorders and for individual psychiatric symptoms.

Research Update rTMS for Treatment of Anxiety – Research Protocol Review and rTMS System Configuration

rTMS bei Tinnitus

Background:
Repetitive transcranial magnetic stimulation (rTMS) applied over left
temporoparietal cortex has been reported to have a long-term therapeutic effect on
tinnitus. We compare the impact of 1 and 25 Hz rTMS delivered either contralateral
or ipsilateral to symptoms in 62 patients with unilateral chronic tinnitus.
Material and methods:
Patients were randomly assigned to one of four treatment
groups: with stimulation at 1 or 25 Hz applied either ipsilateral or contralateral to
symptoms. Two thousand pulses per session were given daily for 2 weeks. Changes in
tinnitus handicap inventory (THI), self-rating scores of loudness, awareness, and
annoyance were measured monthly for 10 months. Duration of residual inhibition
(RI) and psychiatric morbidity were evaluated monthly for 3 months.
Results:
There was a significant main effect of time (P< 0.0001) and a significant time · side interaction ( P= 0.032) between groups. This was because of the fact that
contralateral stimulation had a greater effect on THI than ipsilateral stimulation; it
was also superior to left side stimulation (P= 0.027). Ratings of loudness improved
more after contralateral rTMS (P= 0.037). Twenty patients had no remaining tin-
nitus after 3 months; the remainder had a significant increase in RI. Patients with the
shortest history of tinnitus tended to respond better to rTMS. There was a significant
correlation between changes in THI score and changes in Hamilton anxiety and
depression scores.
Conclusion:
Ten daily treatments of 1 and 25 Hz rTMS contralateral to the side of
tinnitus have a greater beneficial effect on symptoms than either ipsilateral or left side
stimulation.

Chronic tinnitus is associated with neuroplastic changes in auditory and non-auditory
cortical areas. About 10 years ago, repetitive transcranial magnetic stimulation (rTMS)
of auditory and prefrontal cortex was introduced as potential treatment for tinnitus. The
resulting changes in tinnitus loudness are interpreted in the context of rTMS induced
activity changes (neuroplasticity). Here, we investigate the effect of single rTMS sessions on oscillatory power to probe the capacity of rTMS to interfere with tinnitus-specific cortical plasticity. We measured 20 patients with bilateral chronic tinnitus and 20 healthy controls comparable for age, sex, handedness, and hearing level with a 63-channel electroencephalography (EEG) system. Educational level, intelligence, depressivity and hyperacusis were controlled for by analysis of covariance. Different rTMS protocols were tested: Left and right temporal and left and right prefrontal cortices were each stimulated with 200 pulses at 1 Hz and with an intensity of 60% stimulator output.
Stimulation of central parietal cortex with 6-fold reduced intensity (inverted passive-cooled coil) served as sham condition. Before and after each rTMS protocol 5 min of resting state EEG were recorded. The order of rTMS protocols was randomized over two sessions with 1 week interval in between. Analyses on electrode level showed that people with and without tinnitus differed in their response to left temporal and right frontal stimulation. In tinnitus patients left temporal rTMS decreased frontal theta and delta and increased beta2 power, whereas right frontal rTMS decreased right temporal beta3 and gamma power. No changes or increases were observed in the control group. Only non-systematic changes in tinnitus loudness were induced by single sessions of rTMS. This is the first study to show tinnitus-related alterations of neuroplasticity that were specific to stimulation site and oscillatory frequency. The observed effects can be interpreted within the thalamocortical dysrhythmia model assuming that slow waves represent processes of deafferentiation and that high frequencies might be indicators for tinnitus loudness. Moreover our findings confirm the role of the left temporal and the right frontal areas as relevant hubs in tinnitus related neuronal network. Our results underscore the value of combined TMS-EEG measurements for investigating disease related changes in neuroplasticity.

Magnetstimulation und Schmerz

Background and objective: A single session of repetitive transcranial magnetic stimulation (rTMS) over motor cortex had been reported to produce short term relief of some types of chronic pain. The present study investigated whether five consecutive days of rTMS would lead to longer lasting pain relief in unilateral chronic intractable neuropathic pain. Patients and methods: Forty eight patients with therapy resistant chronic unilateral pain syndromes (24 each with trigeminal neuralgia (TGN) and post-stroke pain syndrome (PSP)) participated. Fourteen from each group received 10 minutes real rTMS over the hand area of motor cortex (20 Hz, 10610 s trains, intensity 80% of motor threshold) every day for five consecutive days. The remaining patients received sham stimulation. Pain was assessed using a visual analogue scale (VAS) and the Leeds assessment of neuropathic symptoms and signs (LANSS) scale, before, after the first, fourth, and fifth sessions, and two weeks after the last session. Results: No significant differences were found in basal pain ratings between patients receiving real- and sham-rTMS. However, a two factor ANOVA revealed a significant ‘‘¡ TMS’’ 6 ‘‘time’’ interaction indicating that real and sham rTMS had different effects on the VAS and LANSS scales. Post hoc testing showed that in both groups of patients, real-rTMS led to a greater improvement in scales than sham-rTMS, evident even two weeks after the end of the treatment. No patient experienced adverse effects. Conclusion: These results confirm that five daily sessions of rTMS over motor cortex can produce longlasting pain relief in patients with TGN or PSP.

Non-invasive unilateral repetitive transcranial magnetic stimulation (rTMS) of the motor cortex induces analgesic effects in focal chronic pain syndromes, probably by modifying central pain modulatory systems. Neuroimaging studies have shown bilateral activation of a large number of structures, including some of those involved in pain processing, suggesting that such stimulation may induce generalized analgesic effects.The goal of this study was to assess the effects of unilateral rTMS of the motor cortex on chronic widespread pain in patients with fibromyalgia. Thirty patients with fibromyalgia syndrome (age: 52.67.9) were randomly assigned, in a double-blind fashion, to two groups, one receiving active rTMS (n = 15) and the other sham stimulation (n = 15), applied to the left primary motor cortex in 10 daily sessions. The primary outcome measure was self-reported average pain inten- sity over the last 24 h, measured at baseline, daily during the stimulation period and then 15, 30 and 60 days after the first stimulation. Other outcome measures included: sensory and affective pain scores for the McGill pain Questionnaire, quality of life (assessed with the pain interference items of the Brief Pain Inventory and the Fibromyalgia Impact Questionnaire), mood and anxiety (assessed with the Hamilton Depression Rating Scale, the Beck Depression Inventory and the Hospital Anxiety and Depression Scale).We also assessed the effects of rTMS on the pressure pain threshold at tender points ipsi- and contralateral to stimulation. Follow-up data were obtained for all the patients on days 15 and 30 and for 26 patients (13 in each treatment group) on day 60. Active rTMS significantly reduced pain and improved several aspects of quality of life (including fatigue, morning tired- ness, general activity, walking and sleep) for up to 2 weeks after treatment had ended.The analgesic effects were observed from the fifth stimulation onwards and were not related to changes in mood or anxiety.The effects of rTMS were more long-lasting for affective than for sensory pain, suggesting differential effects on brain struc- tures involved in pain perception. Only few minor and transient side effects were reported during the stimula- tion period. Our data indicate that unilateral rTMS of the motor cortex induces a long-lasting decrease in chronic widespread pain and may therefore constitute an effective alternative analgesic treatment for fibromyalgia.

Repetitive Transcranial Magnetic Stimulation is Efficacious as an Add-On to Pharmacological Therapy in Complex Regional Pain Syndrome (CRPS) Type I

Abstract:
Single-session repetitive transcranial magnetic stimulation (rTMS) of the motor cortex
(M1) is effective in the treatment of chronic pain patients, but the analgesic effect of repeated sessions is still unknown. We evaluated the effects of rTMS in patients with refractory pain due to complex regional pain syndrome (CRPS) type I. Twenty-three patients presenting CRPS type I of 1 upper limb were treated with the best medical treatment (analgesics and adjuvant medications, physical therapy) plus 10 daily sessions of either real (r-) or sham (s-) 10Hz rTMS to the motor cortex (M1). Patients were assessed daily and after 1 week and 3 months after the last session using the Visual Analogical Scale (VAS), the McGill Pain Questionnaire (MPQ), the Health Survey-36 (SF-36), and the Hamilton Depression (HDRS). During treatment there was a significant reduction in the VAS scores favoring the r-rTMS group, mean reduction of 4.65 cm (50.9%) against 2.18 cm (24.7%) in the s-rTMS group. The highest reduction occurred at the tenth session and correlated to improvement in the affective and emotional subscores of the MPQ and SF-36. Real rTMS to the M1 produced anal-gesic effects and positive changes in affective aspects of pain in CRPS patients during the period of stimulation.
Perspective:
This study shows an efficacy of repetitive sessions of high-frequency rTMS as an add-on therapy to refractory CRPS type I patients. It had a positive effect in different aspects of pain (sensory-discriminative and emotional-affective). It opens the perspective for the clinical use of this technique.

Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia

We assessed for the first time the long-term maintenance of repetitive transcranial magnetic stimulation (rTMS)-induced analgesia in patients with chronic widespread pain due to fibromyalgia. Forty consecutive patients were randomly assigned, in a double-blind fashion, to 2 groups: one receiving active rTMS (n = 20) and the other, sham stimulation (n = 20), applied to the left primary motor cortex. The stimulation protocol consisted of 14 sessions: an ‘‘induction phase’’ of 5 daily sessions followed by a ‘‘maintenance phase’’ of 3 sessions a week apart, 3 sessions a fortnight apart, and 3 sessions a month apart. The primary outcome was average pain intensity over the last 24 hours, measured before each stimulation from day 1 to week 21 and at week 25 (1 month after the last stimulation). Other outcomes measured included quality of life, mood and anxiety, and several parameters of motor cortical excitability.
Thirty patients completed the study (14 in the sham stimulation group and 16 in the active stimulation group). Active rTMS significantly reduced pain intensity from day 5 to week 25. These analgesic effects were associated with a long-term improvement in items related to quality of life (including fatigue, morning tiredness, general activity, walking, and sleep) and were directly correlated with changes in intracortical inhibition. In conclusion, these results suggest that TMS may be a valuable and safe new
therapeutic option in patients with fibromyalgia.

Background: Repetitive transcranial magnetic stimulation (rTMS) has shown promise in the alleviation of acute and chronic pain by altering the activity of cortical areas involved in pain sensation. However, current single-coil rTMS technology only allows for effects in surface cortical structures. The ability to affect activity in certain deep brain structures may however, allow for a better efficacy, safety, and tolerability. This study used PET imaging to determine whether a novel multi-coil rTMS would allow for preferential targeting of the dorsal anterior cingulate cortex (dACC), an area always activated with pain, and to provide preliminary evidence as to whether this targeted approach would allow for efficacious, safe, and tolerable analgesia both in a volunteer/acute pain model as well as in fibromyalgia chronic pain patients. Methods: Part 1: Different coil configurations were tested in a placebo-controlled crossover design in volunteers (N = 16). Tonic pain was induced using a capsaicin/thermal pain model and functional brain imaging was performed by means of H125O positron emission tomography – computed tomography (PET/CT) scans. Differences in NRS pain ratings between TMS and sham treatment (NRSTMS-NRSplacebo) which were recorded each minute during the 10 minute PET scans. Part 2: 16 fibromyalgia patients were subjected to 20 multi-coil rTMS treatments over 4 weeks and effects on standard pain scales (Brief Pain Inventory, item 5, i.e. average pain NRS over the last 24 hours) were recorded. Results: A single 30 minute session using one of 3 tested rTMS coil configurations operated at 1 Hz consistently produced robust reduction (mean 70% on NRS scale) in evoked pain in volunteers. In fibromyalgia patients, the 20 rTMS sessions also produced a significant pain inhibition (43% reduction in NRS pain over last 24 hours), but only when operated at 10 Hz. This degree of pain control was maintained for at least 4 weeks after the final session. Conclusion: Multi-coil rTMS may be a safe and effective treatment option for acute as well as for chronic pain, such as that accompanying fibromyalgia. Further studies are necessary to optimize configurations and settings as well as to elucidate the mechanisms that lead to the long-lasting pain control produced by these treatments.

We investigated the role of glutamate N-methyl-D-aspartate (NMDA) receptors in the analgesic effects induced by repetitive transcranial magnetic stimulation (rTMS). In a randomized, double-blind, crossover study, we compared the effects of ketamine and placebo on the analgesic effects of motor cortex (M1) or dorsolateral prefrontal cortex/premotor cortex (DLPFC/PMC) stimulation. Three groups of 12 healthy volunteers underwent active rTMS (10 Hz, 80% resting motor threshold, 1,500 pulses per session) of the right M1, active stimulation of the right DLPFC/PMC, or sham stimulation during 2 experimental sessions 2 weeks apart. Cold pain thresholds were measured on the left thenar eminence before and 1 hour after cortical stimulation, to evaluate the analgesic effects of rTMS. Ketamine (0.15 mg/kg in a 10-minute bolus
followed by continuous infusion of 6 l g/kg per minute until the end of rTMS) or placebo (saline) were administered intravenously during cortical stimulation. We also systematically measured cortical excitability parameters (resting motor threshold, suprathreshold motor-evoked potentials, short intracortical inhibition, and intracortical facilitation) before and after treatment, to investigate the possible relationship between changes in cortical excitability and rTMS-induced analgesia. Ketamine injection signi-
cantly decreased the analgesic effects of both M1 and DLPFC/PMC stimulation. The decrease in the analgesic effect of rTMS was not associated with changes in cortical excitability parameters, which were not inuenced by rTMS following the administration of either saline or ketamine. Thus, rTMS-induced analgesia depends on glutamate NMDA receptors and may involve long-term potentiation-like mechanisms.

Into the Island: A new technique of non-invasive cortical stimulation of the insula

Summary
Study aim.
We describe a new neuronavigation-guided technique to target the posterior-
superior insula (PSI) using a cooled-double-cone coil for deep cortical stimulation.

Introduction
Despite the analgesic effects brought about by repetitive transcranial magnetic
stimulation (TMS) to the primary motor and prefrontal cortices, a signicant proportion of
patients remain symptomatic. This encouraged the search for new targets that may provide stronger pain relief. There is growing evidence that the posterior insula is implicated in the integration of painful stimuli in different pain syndromes and in homeostatic thermal integration.

Methods
The primary motor cortex representation of the lower leg was used to calculate the
motor threshold and thus, estimate the intensity of PSI stimulation.

Results
Seven healthy volunteers were stimulated at 10 Hz to the right PSI and showed sub-
jective changes in cold perception. The technique was safe and well tolerated.

Conclusions
The right posterior-superior insula is worth being considered in future studies as
a possible target for rTMS stimulation in chronic pain patients.

Objective:
To determine the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) combined with occupational therapy (OT) on the spasticity of the hemiparetic upper limb after stroke.

Subjects and methods:
The study subjects were 39 post-stroke patients with spastic upper limb hemiparesis (age: 56.5 16.0 years, time after onset: 50.3 37.8 months). At admission, the severity of hemiparesis was categorized as Brunnstrom stage 3–5 for hand–fingers. During 15-day hospitalization, each patient received 22 sessions of low-frequency rTMS applied to the non-lesional hemisphere and OT (one-to-one training and self-training). The spasticity of finger and wrist flexors of the affected upper limb was evaluated using the modified Ashworth scale (MAS) on the day of admission and discharge and 4 weeks after discharge. Each subject underwent Fugl-Meyer Assessment (FMA) and Wolf Motor Function Test (WMFT).

Results:
The low-frequency rTMS/OT protocol significantly decreased the MAS scores for both finger and wrist flexors at discharge and at 4 weeks after discharge. In addition, the low-frequency rTMS/OT protocol significantly increased the FMA score and shortened the WMFT performance time.

Conclusions:
The 15-day in-patient protocol of low-frequency rTMS/OT is potentially suitable for reducing spasticity as well as improving motor function on the affected upper limb after stroke.

Theta burst stimulation reduces disability during the activities of daily living in spatial neglect

Left-sided spatial neglect is a common neurological syndrome following right-hemispheric stroke. The presence of spatial neglect is a powerful predictor of poor rehabilitation outcome. In one influential account of spatial neglect, interhemispheric inhibition is impaired and leads to a pathological hyperactivity in the contralesional hemisphere, resulting in a biased attentional allocation towards the right hemifield. Inhibitory transcranial magnetic stimulation can reduce the hyperactivity of the contralesional, intact hemisphere and thereby improve spatial neglect symptoms. However, it is not known whether this improvement is also relevant to the activities of daily living during spontaneous behaviour. The primary aim of the present study was to investigate whether the repeated application of continuous theta burst stimulation trains could ameliorate spatial neglect on a quantitative measure of the activities of daily living during spontaneous behaviour. We applied the Catherine Bergego Scale, a standardized observation questionnaire that can validly and reliably detect the presence and severity of spatial neglect during the activities of daily living. Eight trains of continuous theta burst stimulation were applied over two consecutive days on the contralesional, left posterior parietal cortex in patients suffering from subacute left spatial neglect, in a randomized, double-blind, sham-controlled design, which also included a control group of neglect patients without stimulation. The results showed a 37% improvement in the spontaneous everyday behaviour of the neglect patients after the repeated application of continuous theta burst stimulation. Remarkably, the improvement persisted for at least 3 weeks after stimulation. The amelioration of spatial neglect symptoms in the activities of daily living was also generally accompanied by significantly better performance in the neuropsychological tests. No significant amelioration in symptoms was observed after sham stimulation or in the control group without stimulation. These results provide Class I evidence that continuous theta burst stimulation is a viable add-on therapy in neglect rehabilitation that facilitates recovery of normal everyday behaviour.

Background:
The purpose of this study was to determine whether local injection of botulinum toxin type A (BoNT-A) into the spastic muscles has any added benefits to repeti- tive transcranial magnetic stimulation (RTMS)/occupational therapy (OT) in patients with spastic upper limb hemiparesis.

Methods:
The study subjects of 80 post-stroke patients with spastic upper limb hemiparesis (age: 60.2 ± 13.0 years, time after stroke: 55.3 ± 43.0 months), were divided into the
BoNT-A plus RTMS/OT group and RTMS/OT group. BoNT-A was injected into the spastic muscles (total dose: 240 units) before RTMS/OT. The latter included 12 sessions of 40 min RTMS over the non-lesional hemisphere and 240-min intensive OT daily over 15 days. Spasticity was evaluated by the modified Ashworth scale (MAS) and the motor function of the affected upper limb was evaluated serially with Fugl-Meyer Assessment and Wolf Motor Function Tests.

Conclusions:
The triple-element protocol of local injection of BoNT-A into spastic finger muscles, RTMS and intensive OT, is a promising therapeutic program for post-stroke spastic upper limb hemiparesis, although its significance should be confirmed in randomized, placebo-controlled trials.

rTMS bei Schreibkrampf

Modulation of sensorimotor integration in patients with writer’s cramp by subthreshold low-frequency rTMS over the premotor cortex

Background: WC is a task-specific focal dystonia. Many studies have shown that the processing of sensory inputs is disturbed in dystonia. Subthreshold low-frequency rTMS over the premotor cortex has been shown to improve the clinical signs of WC. Aims: To characterize the abnormalities of sensorimotor integration in writer’s cramp (WC) and to analyze the influence of premotor repetitive transcranial magnetic stimulation (rTMS) on sensorimotor integration. Methods: We studied 10 WC patients and 10 agematched control subjects. Motor evoked potentials (MEP) were recorded from bilateral abductor pollicis brevis, first dorsal interosseus, flexor carpi radialis and extensor carpi radialis muscles. TMS was applied using a focal coil over the hand motor area with an intensity of 120% of the rest motor threshold (RMT). Sensorimotor integration was probed by analyzing the changes in MEP amplitude when conditioning the cortical motor stimulation with a peripheral nerve (median nerve (MN) or index finger) stimulation, using different conditioning-test (C-T) intervals (19, 21, 23, 25, 50, 100, 200, 300, 500, and 1000 ms). Sensorimotor integration was studied before and after 1 Hz premotor cortex rTMS at 90% RMT. Results: Conditioning peripheral stimulation significantly modulated MEP size in all muscles of normal controls and WC patients. Control subjects exhibited an inhibitory effect at the C-T interval of 200 ms after both MN and index finger stimulation, and a facilitatory effect at the CT interval of 50 ms only after MN stimulation. In WC patients, facilitatory effect was decreased in the symptomatic side. After rTMS, sensorimotor integration tended to be normalized. Conclusion: The processing of proprioceptive inputs is disturbed in WC. Premotor rTMS may restore a normal sensorimotor integration.

Transcranielle Magnetstimulation bei Drogenabusus

Recent animal studies demonstrate that compulsive cocaine seeking strongly reduces prelimbic frontal cortex activity, while optogenetic stimulation of this brain area significantly inhibits compulsive cocaine seeking, providing a strong rationale for applying brain stimulation to reduce cocaine consumption. Thus, we employed repetitive transcranial magnetic stimulation (rTMS), to test if dorsolateral prefrontal cortex (DLPFC) stimulation might prevent cocaine use in humans. Thirty-two cocaine-addicted patients were randomly assigned to either the experimental group (rTMS) on the left DLPFC, or to a control group (pharmacological agents) during a 29-day study (Stage 1). This was followed by a 63-day follow-up (Stage 2), during which all participants were offered rTMS treatment. Amongst the patients who completed Stage 1, 16 were in the rTMS group (100%) and 13 in the control group (81%). No significant adverse events were noted. During Stage 1, there were a significantly higher number of cocaine-free urine drug tests in the rTMS group compared to control ( p = 0.004). Craving for cocaine was also significantly lower in the rTMS group compared to the controls (p=0.038). Out of 13 patients who completed Stage 1 in the control group, 10 patients received rTMS treatment during Stage 2 and showed significant improvement with favorable outcomes becoming comparable to those of the rTMS group. The present preliminary findings support the safety of rTMS in cocaine-addicted patients, and suggest its potential therapeutic role for rTMS-driven PFC stimulation in reducing cocaine use, providing a strong rationale for developing larger placebo-controlled
studies.

IRCCS San Camillo, Venezia, Italy b National Institute on Drug Abuse (NIDA) Intramural Research Program, Baltimore, MD, United States c Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD, United States d Center for Alcohol and Addiction Studies, Brown University, Providence, RI, United States e Department of Neuroscience, University of Padua, Italy f Solomon H. Snyder Neuroscience Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States g Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Transcranielle Magnetstimulation bei Demenz

Adjunctive treatment with high frequency repetitive transcranial magnetic stimulation for the behavioral and psychological symptoms of patients with Alzheimer’s disease: a randomized, double-blind, sham-controlled study

Background:
Behavioral and psychological symptoms of dementia (BPSD) occur in 70-90% of patients at
different stages of Alzheimer’s Disease (AD), but the available methods for managing these problems are of limited effectiveness.

Aim:
Assess the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS), applied over the left dorsolateral prefrontal cortex (DLPFC), on BPSD and cognitive function in persons with AD.

Methods:
Fifty-four patients with AD and accompanying BPSD were randomly divided into an intervention
group (n=27) and a control group (n=27). In addition to standard antipsychotic treatment, the intervention group was treated with 20Hz rTMS five days a week for four weeks, while the control group was treated with sham rTMS. The Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD), the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog), and the Treatment Emergent Symptom Scale (TESS) were administered by raters who were blind to the group assignment of patients before and after four weeks of treatment.

Results:
Twenty-six subjects from each group completed the study. After four weeks of antipsychotic
treatment with adjunctive real or sham rTMS treatment, the mean (sd) total BEHAVE-AD scores and mean total ADAS-Cog scores of both groups significantly decreased from baseline. After adjusting for baseline values, the intervention group had significantly lower scores (i.e., greater improvement) than the control group on the BEHAVE-AD total score, on five of the seven BEHAVE-AD factor scores (activity disturbances, diurnal rhythm, aggressiveness, affective disturbances, anxieties and phobias), on the ADAS-Cog total score, and on all four ADAS-Cog factor scores (memory, language, constructional praxis, and attention). The proportion of individuals whose behavioral symptoms met a predetermined level of improvement (i.e., a drop in BEHAVE-AD total score of > 30% from baseline) in the intervention group was greater than that in the
control group (73.1% vs. 42.3%, X2=5.04, p=0.025).

Conclusion:
Compared to treatment of AD with low-dose antipsychotic medications alone, the combination
of low-dose antipsychotic medication with adjunctive treatment with high frequency rTMS can significantly improve both cognitive functioning and the behavioral and psychological symptoms that often accompany AD.

Repetitive periphere Magnetstimulation bei Ellbogenverletzung

Abstract To investigate the role repetitive peripheral magnetic stimulation (RPMS) on the postural component of motor performances, the long-lasting modulatory effect of RPMS on the stabilization of the elbow joint was examine in 13 healthy subjects. The resistance against very slow passive movements in the relaxed state was recorded simultaneously with the electromyogram (EMG) of the forearm extensor and flexor muscles. The experiments show that RPMS performed on the forearm flexor muscles increased the degree of stabilization of the elbow joint, whereas RPMS on the forearm extensor muscles caused a decrease in stabilization. This leads to the assumption that the postural component of motor tasks depends on the motor task itself: motor tasks like manipulation, pointing or grasping which are fine skilled movements require an increase in stabilization wile goal-directed movements require a decrease in stabilization. Therefore RPMS is involved in a sensorimotor integration and may modulate the motor program at the cortical level. Keywords: Sensorimotor control - Repetitive peripheral magnetic stimulation - Neuromodulation - Postural component of motor tasks - Joint stabilization - Muscle spindle

In central paresis the proprioceptive input to the CNS from the paretic muscle is diminished. To re-activate patterns of lost movements, we induce controlled muscle contractions by repetitive peripheral magnetic stimulation (RPMS). As we could already show after RPMS of plegic finger extensors, hemi paretic patients could perform rapid finger extension movements with larger displacement amplitude and velocity at diminished amounts of activity (EMG). In order to investigate the detailed mechanism of RPMS a PET study (8 patients) and a pure cognition test (14 patients) were performed. PET scans showed an increased activation after RPMS treatment of fronto parietal areas primarily involved in goal directed sensor motor control. The pure cognitive test was evaluating the ability to recognize the perception of various tactile stimuli. After RPMS the recognition errors were significantly diminished.

Weitere Studien

High-frequency magnetic stimulation (HFMS) can elicit N-methyl-D-aspartate (NMDA) receptor-dependent long-term potentiation (LTP) at Schaffer collateral-CA1 pyramidal cell synapses. Here, we investigated the priming effect of HFMS on the subsequent
magnitude of electrically induced LTP in the CA1 region of rat hippocampal slices using field excitatory postsynaptic potential (fEPSP) recordings. In control slices, electrical high-frequency conditioning stimulation (CS) could reliably induce LTP. In contrast,
the same CS protocol resulted in long-term depression when HFMS was delivered to the slice 30 min prior to the electrical stimulation. HFMS-priming was diminished when applied in the presence of the metabotropic glutamate receptor antagonists (RS)-alpha-methylserine-O-phosphate (MSOP) and (RS)-alpha-methyl-4-carboxyphenylglycine (MCPG). Moreover, when HFMS was delivered in the presence of the NMDA receptor-antagonist D-2-amino-5-phosphonovalerate (50 alpha M), CS-induced electrical LTP was againas high as under control conditions in slices without priming. These results demonstrate that HFMS significantly reduced the propensity of subsequent electrical LTP and show that both metabotropic glutamate and NMDA receptor activation were involved in this form of HFMS-induced metaplasticity.